DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

Abstract

triple-negative breast cancer (tnBc) is a subtype of breast cancer unresponsive to traditional receptortargeted treatments, leading to a disproportionate number of deaths. invasive breast cancer is believed to evolve from non-invasive ductal carcinoma in situ (DciS). Detection of triple-negative DciS (tn-DciS) is challenging, therefore strategies to study molecular events governing progression of pre-invasive tn-DciS to invasive tnBc are needed. Here, we study a canine tn-DciS progression and investigate the DnA methylation landscape of normal breast tissue, atypical ductal hyperplasia (ADH), DciS and invasive breast cancer. We report hypo-and hypermethylation of genes within functional categories related to cancer such as transcriptional regulation, apoptosis, signal transduction, and cell migration. DnA methylation changes associated with cancer-related genes become more pronounced at invasive breast cancer stage. Importantly, we identify invasive-only and DCIS-specific DNA methylation alterations that could potentially determine which lesions progress to invasive cancer and which could remain as pre-invasive DciS. changes in DnA methylation during tn-DciS progression in this canine model correspond with gene expression patterns in human breast tissues. this study provides evidence for utilizing methylation status of gene candidates to define late-stage (DCIS and invasive), invasive stage only or DciS stage only of tn-DciS progression. Breast cancer is classified into subtypes based on the expression of growth factor receptors including the estrogen receptor (ER), the progesterone receptor (PR), and the receptor for human epidermal growth factor (HER-2) 1. Growth of breast tumors expressing any of these receptors may be controlled effectively by treatment in the adjuvant setting with receptor-targeted drugs 2. However, breast tumors that do not express any of these receptors have no known effective adjuvant treatment capable of controlling tumor growth. Such tumors are referred to as triple-negative breast cancers (TNBC) and are the most aggressive and lethal of all breast malignancies 2. TNBC accounts for 15% of breast cancer cases and a disproportionate percentage of breast cancer deaths among women 3. It has been shown that patients with TNBC have poor prognosis and shorter median time to relapse compared to patients with other subtypes of breast cancer 4. Ductal carcinoma in situ (DCIS) is defined as a non-invasive overgrowth of cells characterized by high proliferation within the breast ductal system. Studies suggest that triple-negative DCIS (TN-DCIS), a rare type of DCIS, is a precursor stage of invasive breast cancer 5,6. Therefore, early detection of TN-DCIS is important in preventing breast cancer cases that may progress to triple negative invasive carcinoma. However, TN-DCIS is challenging to detect at early stage in humans 7. Despite efforts to use immunohistochemistry to measure receptor expression in scientific studies of human DCIS tissues, detection of receptor status, including ER, is not routi...

Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via Integrating ERK/JNK Pathway

“…Methylation pro les can be used as clinical biomarkers to predict drug response and prognosis of breast cancer (33,34). DNA methylation alterations associated with cancer-related genes have become more pronounced and acted as the effective biomarker for early diagnosis and disease progression monitoring in the invasive breast tumors (35)(36)(37). The previous research from our group has revealed hypermethylated ST5 in gastric poorly differentiated adenocarcinoma (38).…”

Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via ERK/JNK Pathway

“…Methylation profiles can be used as clinical biomarkers to predict drug response and prognosis of breast cancer (41,42). Of note, DNA methylation of tumor suppressors have become the effective biomarker for early diagnosis and disease progression monitoring in the invasive breast tumors (43)(44)(45). Among the DENN protein family, promoter hypermethylation-mediated the downregulation of DENND2D is associated with early recurrence of hepatocellular carcinoma and gastric cancer (16,17).…”

Canine and feline in situ mammary carcinoma: A comparative review

“…Beetch et al in 2020, following their former works on DCIS histopathology, clinical outcome, and imaging, 4,37,39 assessed DNA methylation alterations through the progression of canine triple-negative DCIS to triple-negative invasive mammary carcinoma. 6 Functional analysis of differentially methylated genes in DCIS and invasive tumors showed alteration in various processes commonly dysregulated in cancer, such as cell cycle progression, transcriptional regulation, apoptosis, and cellular signaling. 7…”